Pomegranate fruit dry rot is caused by Coniella granati, also referred as Pilidiella granati. In order to decipher the induced responses of mature pomegranates inoculated with the pathogen, an RNA-seq analysis was employed. A high number of differentially expressed genes (DEGs) were observed through a three-time series inoculation period. The transcriptional reprogramming was time-dependent, whereas the majority of DEGs were suppressed and the expression patterns of specific genes may facilitate the pathogen colonization at 1 day after inoculation (dai). In contrast, at 2 dai and mainly thereafter at 3 dai, defense responses were partially triggered in delay. Particularly, DEGs were mainly upregulated at the latest time point. Among them, specific DEGs involved in cell wall modification and degradation processes, pathogen recognition and signaling transduction cascades, activation of specific defense and metabolite biosynthesis-related genes, as well in induction of particular families of transcriptional factors, may constitute crucial components of a defense recruiting strategy employed by pomegranate fruit upon C. granati challenge. Overall, our findings provide novel insights to the compatible interaction of pomegranates—C. granati and lay the foundations for establishing integrated pest management (IPM) strategies involving advanced approaches, such as gene editing or molecular breeding programs for disease resistance, according to European Union (EU) goals.